Since the 1940s, over half of the anticancer drugs developed are natural products or inspired by natural products. Anticancer drugs have traditionally been developed from compounds with broad potency against multiple cancer cell lines, but molecules that are selective for a particular type of cancer offer considerable promise. These selective compounds will enable a personalized cancer treatment that could reduce or eliminate the side effects associated with current generation cancer treatments. Mahanine is a naturally occurring compound that has demonstrated highly selective activity against leukemia cell lines. This proposal describes the synthesis of mahanine and novel analogues utilizing a 1) N-arylation and oxidative biaryl coupling and 2) Crombie chromene synthesis. With an efficient, scalable, and flexible route to mahanine, a small library of analogues will be synthesized to construct a detailed structure activity relationship. This information will facilitate the discovery of compounds with improved activity and selectivity. These more active analogues will provide a candidate for potential therapeutic use. In addition, detailed mechanistic studies will be performed in leukemia cells to precisely determine the mode of action and cellular target. Overall, this research will advance the study of leukemia and treatments for this deadly disease. PUBLIC HEALTH RELEVANCE: Mahanine has demonstrated high potency and selectivity for leukemia cell lines. The synthesis of novel analogues will provide insight into the important structural features of mahanine and could provide a more efficacious therapeutic. In addition, determining the cellular target of mahanine in leukemia cells could identify new approaches for leukemia treatment.